Miniaturized sample scanning mass analyzer

ABSTRACT

A mass spectrometer that includes an ionizing source, a sample holder arranged in a beam path of the ionizing source, an ion detector disposed to receive ions extracted from a sample when held by the sample holder and irradiated by the ionizing source. The mass spectrometer also includes an extraction electrode arranged proximate to the sample holder, and a drift tube arranged between the extraction electrode and the ion detector. In the mass spectrometer, the extraction electrode and the drift tube are movable together relative to the sample holder, which is held at a fixed position.

RELATED APPLICATIONS

This Application is the U.S. National Phase Filing of PCT/US03/10814,filed Apr. 9, 2003, which is based on U.S. Provisional Application60/371,443, filed Apr. 10, 2002, the entire contents of both of whichApplications are hereby incorporated by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

The present invention was conceived during the course of work supportedby grant No. R01 RR08912 from the National Institutes of Health, grantNo. DABT163-99-1-0006 and grant No. BAA00-09-013 from DARPA.

BACKGROUND OF INVENTION

1. Field of Invention

The present invention relates to a mass spectrometer in general and inparticular to a miniaturized sample scanning mass spectrometer.

2. Description of Related Art

Mass spectrometers are instruments that are used to determine thechemical composition of substances and the structures of molecules. Ingeneral they consist of an ion source where neutral molecules areionized, a mass analyzer where ions are separated according to theirmass/charge ratio, and a detector. Mass analyzers come in a variety oftypes, including magnetic field (B) instruments, combined electrical andmagnetic field or double-focusing instruments (EB or BE), quadrupoleelectric field (Q) instruments, and time-of-flight (TOF) instruments. Inaddition, two or more analyzers may be combined in a single instrumentto produce tandem (MS/MS) mass spectrometers. These include tripleanalyzers (EBE), four sector mass spectrometers (EBEB or BEEB), triplequadrupoles (QqQ) and hybrids (such as the EBqQ).

In tandem mass spectrometers, the first mass analyzer is generally usedto select a precursor ion from among the ions normally observed in amass spectrum. Fragmentation is then induced in a region located betweenthe mass analyzers, and the second mass analyzer is used to provide amass spectrum of the product ions. Tandem mass spectrometers may beutilized for ion structure studies by establishing the relationshipbetween a series of molecular and fragment precursor ions and theirproducts.

Alternatively, they are now commonly used to determine the structures ofbiological molecules in complex mixtures that are not completelyfractionated by chromatographic methods. These may include mixtures of(for example) peptides, glycopeptides or glycolipids. In the case ofpeptides, fragmentation produces information on the amino acid sequence.

One type of mass spectrometers is time-of-flight (TOF) massspectrometers. The simplest version of a time-of-flight massspectrometer, illustrated in FIG. 1 (Cotter, Robert J., Time-of-FlightMass Spectrometry: Instrumentation and Applications in BiologicalResearch, American Chemical Society, Washington, D.C., 1997), the entirecontents of which is hereby incorporated by reference, consists of ashort source region 10, a longer field-free drift region 12 and adetector 14. Ions are formed and accelerated to their final kineticenergies in the short source region 10 by an electric field defined byvoltages on a backing plate 16 and drawout grid 18. The longerfield-free drift region 12 is bounded by drawout grid 18 and an exitgrid 20.

In the most common configuration, the drawout grid 18 and exit grid 20(and therefore the entire drift length) are at ground potential, thevoltage on the backing plate 16 is V, and the ions are accelerated inthe source region to an energy: mv²/2=z eV, where m is the mass of theion, v is its velocity, z the number of charges, and e is the charge onan electron. The ions then pass through the drift region 12 and their(approximate) flight time(s) is given by the formula:t=[(m/z)/2 eV]^(1/2) D  (I)which shows a square root dependence upon mass. Typically, the length sof source region 10 is of the order of 0.5 cm, while drift lengths (D)ranges from 15 cm to 8 meters. Accelerating voltages (V) can range froma few hundred volts to 30 kV, and flight time are of the order of 5 to100 microseconds. Generally, the accelerating voltage is selected to berelatively high in order to minimize the effects on mass resolutionarising from initial kinetic energies and to enable the detection oflarge ions. For example, the accelerating voltage of 20 KV (asillustrated, for example, in FIG. 1) has been found to be sufficient fordetection of masses in excess of 300 kDaltons.

In recent years, the development of an ionization technique for massspectrometers known as matrix-assisted laser desorption ionization(MALDI) has generated considerable interest in the use of time-of-flightmass spectrometers and in improvement of their performance. MALDI isparticularly effective in ionizing large molecules (e.g. peptides andproteins, carbohydrates, glycolipids, glycoproteins, andoligonucleotides) as well as other polymers. The TOF mass spectrometerprovides an advantage for MALDI analysis by simultaneously recordingions over a broad mass range, which is the so called multichanneladvantage. In MALDI method of ionization, biomolecules to be analyzedare recrystallized in a solid matrix (e.g., sinnipinic acid, 3-hydroxypicolinic acid, etc.) of a low mass chromophore that its is stronglyabsorbing in the wavelength region of the pulsed laser used to initiateionization. Following absorption of the laser radiation by the matrix,ionization of the analyte molecules occurs as a result of desorption andsubsequent charge exchange processes. In TOF instruments, all ionoptical elements and the detector are enclosed within a vacuum chamberto ensure that ions, once formed, reach the detector without collisionswith the background gas.

A number of techniques have been developed to improve the massresolution of time-of-flight mass spectrometers. Mass resolution isreduced by the initial distributions in the velocity and position of theions when they are formed. The simplest of the techniques used toimprove resolution is the incorporation of a two stage extraction systemto provide space focusing at the detector for an instrument with a longdrift length, and a second order space-focusing for an optimal driftlength (Cotter, R. J., Time-of-Flight Mass Spectrometry: Instrumentationand Applications in Biological Research, American Chemical Society,Washington, D.C. 1997, Boesl, U., Weinkauf, R., Schlag, E. W., Int. J.Mass Spectrom. Ion Processes 112 (1992) 121–166). Pulsed extraction andtime-delayed extraction techniques have been used to address both spaceand energy (velocity) focusing (Wiley, W. C., McLaren, I. H., Rev. Sci.Instrumen. 26 (1955) 1150–1157), including the correlated space/velocitydistributions proposed for MALDI (Colby, S. M., King, T. B., Reilley, J.P., Rapid Commun. Mass Spectrom. 8 (1994) 865).

Other improvements introduced into time-of-flight spectrometers includeminiaturization. An example of a miniaturized TOF mass analyzer is shownin FIG. 2 (Cotter, R. J., The New Time-of-Flight Mass Spectrometery,Anal. Chem 71 (1999) 445A–451A). In mass analyzer instrument 22, samplesare presented as a 10×10 array of sample spots (not shown), mounted on amovable XY stage 24. The length of the ion source, i.e. the distancebetween the surface of movable stage 24 and grid 26, is about 1 inch(2.54 cm) and the length of the drift region 28 is 3 inches (7.6 cm). Inmass spectrometer 22 the sample stage 24 and grid 30 are initially at apotential of 6.45 kV. The grid 26 is connected to the drift tube linerand is held at a potential between −1.9 and 12.2 kV of the first channelplate of a gridless Hamamatsu dual channel plate detector 32 (a dualchannel plate detector is used to increase the gain of the signaldetected). This arrangement eliminates any post acceleration of the ionsinto the detector. Moreover, this arrangement enables the amplifiedcurrent pulse from the detector to be taken near ground potential. Thedrift tube liner is a half inch thin-walled tubing that insures anequipotential (field free) region across the drift length. The samplesurface can be, for example, pulsed from 6.45 kV to 9.75 kV, i.e. usinga 3.3 kV pulse (as illustrated in FIG. 2). The delay time for pulsing isadjusted to provide best focusing to the front channel plate for a givenmass, i.e. maximum mass resolution.

Examples of mass spectra from this instrument are shown in FIGS. 3A and3B. The mass spectrum in FIG. 3A records peptide biomarkers fromBacillus globigii spores. Although this 3-inch mass analyzer isconsiderably smaller than the one meter or larger mass analyzers commonin commercial instruments, the mass range is limited only by the kineticenergy of the ions at the time they reach the detector. In this case,depending on the drift region bias voltage, the kinetic energy is from11.6 keV to 11.95 keV. This is sufficient to record ions as large as 66kdalton molecular ion of bovine serum albumin as shown in the massspectrum of FIG. 3B.

Most commercial MALDI time-of-flight spectrometers now provide analysisof multiple samples loaded at the same time on a sample holder into thevacuum system. The multiple samples on the sample holder include, forexample, “slides” which are one dimensional arrangements from 8 to 30sample spots, large format two-dimensional arrays using 96 or 384samples similar to those used in microtiter plates (Vestal M. L., MassSpectrometer System and Method for Matrix-Assisted Laser DesorptionMeasurements, U.S. Pat. No. RE37485E, Dec. 25, 2001, U.S. Pat. No.5,498,545, Mar. 12, 1996), and higher density microarrays or “samples ona chip.”

An example of a two dimensional array sample holder is shown in FIG. 4.Two dimensional array sample holder 40 holds a plurality of samples 42.The plurality of samples are in this case a two dimensional array ofsamples. The samples on the sample holder are loaded into a vacuumsystem for mass analysis. Once samples are loaded into the vacuum systemof the mass spectrometer, the conventional way to select a sample foranalysis is by moving the sample array. Two dimensional arrays ofsamples on the sample holder 40 are conventionaly mounted on an XYtranslational stage 44, controlled either manually or by a computer-datasystem, to bring each sample into the focal point of a laser beam (theionizer) and the ion extraction optics (not shown in this Figure) whichare for example aligned relative to axis AA′ perpendicular to the planeof the sample holder. In addition to sample selection, movement of thesample stage also enables the selection of an area on each sample wherethe ion signal is more intense. Sample holder 40 is positioned on XYtranslational stage 44 comprising positioning stage represented by arrow44X in the X direction and positioning stage 44Y represented by arrow Yin the Y direction.

In this common arrangement, the laser beam and optics, and the ionextraction optics, flight lengths and detectors and other portions ofthe mass analyzer are stationary within the instruments. It is alsocommon that the sample surface or stage be biased at some highelectrical potential. The high potential is used to define the ionkinetic energy. The flight tube (not shown) is, hence, biased nearground potential. The signal from the ion detector is taken either at orclose to ground through a 50 ohm output.

In this arrangement, the volume required to accommodate a twodimensional sample array is considerable, and defines both the overallinstrument dimensions as well as the capacity of the mechanical andturbomolecular pumping system. Indeed, the sample plate must be movedacross an area 46, defining the footprint of the movement of the XYstage, equal to more than 4 times the area of the sample plate or sampleholder 40 in order to accommodate and analyze each of the samples 42across the entire sample array 40. Furthermore, since the sample stageis biased at some high voltage, an additional space 48 (in the Xdirection) and 49 (in the Y direction) is reserved between the walls ofthe vacuum chamber and the maximum extension of the XY stage such thatthe stage would not come in contact with the wall of the vacuum chamberheld at a ground potential.

For example, for a 127×86 mm sample array format, the total area neededfor the movement of the sample plate alone would be at least 25.4×17.2cm. In addition, the XY stage and its associated drive mechanisms, someor all of which may be at high voltage, contribute to the depth of alarge volume within the mass spectrometer needed to accommodate theentire sample handling system.

SUMMARY OF THE INVENTION

An aspect of the present invention is to provide a mass spectrometerwhich includes an ionizing source, a sample holder arranged in a beampath of the ionizing source, and an ion detector disposed to receiveions extracted from a sample when held by the sample holder andirradiated by the ionizing source. The mass spectrometer also includesan extraction electrode arranged proximate the sample holder, and adrift tube arranged between the extraction electrode and the iondetector. In the mass spectrometer, the extraction electrode and thedrift tube are movable together relative to the sample holder which isheld at a fixed position.

In one embodiment, the mass spectrometer further includes anacceleration electrode disposed between the extraction electrode and thedrift tube. The sample holder can be configured to hold a plurality ofsamples. For example, the plurality of samples can be arranged in asingle row and the sample holder is a tape-like structure. The pluralityof samples can also be arranged in a two-dimensional array on the sampleholder or arranged in a plurality of two dimensional arrays on thesample holder. The sample holder can also be a disk having an openingsuitable for mounting on a rotating assembly. In one embodiment, theplurality of samples are arranged concentrically around the opening andthe extraction electrode and the drift tube can be moved in a radialdirection of the disk relative to the opening.

The mass spectrometer may further include a vacuum chamber and the iondetector, the extraction electrode and the drift tube are disposedinside the vacuum chamber. The sample holder can be, for example, acontinuous tape which is sealingly introduced into the vacuum chamberthrough an opening in a wall of the vacuum chamber or a continuous tapein a tape-cassette and the tape cassette is disposed in the vacuumchamber.

In one embodiment, the mass spectrometer further includes a sampleholder voltage source and the sample holder is connected to the sampleholder voltage source to establish a sample holder voltage potentialrelative to the ground potential.

In another embodiment, the mass spectrometer further includes anextraction voltage source and the extraction electrode is connected tothe extraction voltage source to establish an extraction voltagepotential relative to the voltage potential of the sample holder. Thesample holder voltage potential can be pulsed. Similarly, the extractionelectrode voltage potential can also be pulsed.

In one embodiment, the mass spectrometer further includes a drift tubevoltage source and the drift tube is connected to the drift tube voltagesource to establish a drift tube voltage potential.

In another embodiment, the mass spectrometer further includes anacceleration electrode voltage source and the acceleration electrode isconnected to the acceleration voltage source to establish a voltagepotential substantially equal to a voltage potential of the drift tube.

The ion detector in the mass spectrometer can be anyone of an electronmultiplier, a channeltron, or a micro-channel plate assembly or thelike. In one embodiment, the ion detector is movable together with theextraction electrode and the drift tube relative to the sample holder.In another embodiment, the ion detector is fixed in a substantiallystationary position relative to the sample holder. In this case, themicro-channel plate assembly has a detection area substantiallysubtending an area of the sample holder.

The ionizing source in the mass spectrometer can be, for example, alaser system. In one embodiment, the mass spectrometer further includesa tracking assembly so that the laser can track a movement of theextraction electrode and the drift tube. In this way a laser beamemitted by the laser is directed upon the sample which is directly underthe extraction electrode. In another embodiment, the mass spectrometerfurther includes an optical fiber. The optical fiber can track themovement of the extraction electrode and the drift tube and is used todirect a laser beam emitted by the laser upon the sample which isdirectly under said extraction electrode.

Another aspect of the present invention is to provide a method ofanalyzing a plurality of samples disposed on a sample holder by a massspectrometer comprising an ionizing source, an ion detector, anextraction electrode arranged proximate to the sample holder, and adrift tube arranged between the extraction electrode and the iondetector. The method includes positioning the extraction electrode andthe drift tube above a first sample in the plurality of samples,ionizing the first sample with the ionizing source to form a pluralityof first ions, detecting first ions from the plurality of first ionswith the ion detector and identifying at least a portion of said firstions detected. The method further includes moving at least theextraction electrode and the drift tube together relative to the sampleholder to a second sample of the plurality of samples, ionizing thesecond sample with the ionizing source to form a plurality of secondions, detecting second ions from the plurality of second ions with theion detector, and identifying at least a portion of the second ionsdetected.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects and features of the invention will become moreapparent and more readily appreciated from the following detaileddescription of the presently preferred exemplary embodiments of theinvention, taken in conjunction with the accompanying drawings, ofwhich:

FIG. 1 is a schematic representation of a conventional time-of-flightspectrometer;

FIG. 2 is schematic representation of a conventional miniaturizedtime-of-flight spectrometer;

FIG. 3A is an example of a mass spectrum of B. globigii spores obtainedby the miniaturized mass spectrometer of FIG. 2;

FIG. 3A is an example of a mass spectrum of serum albumin obtained bythe miniaturized mass spectrometer of FIG. 2;

FIG. 4 is a conventional two dimensional array sample holder;

FIG. 5 is a schematic representation of one embodiment of a massspectrometer according to the present invention using a two-dimensionalarray sample holder.

FIG. 6 is a schematic representation of another embodiment of a massspectrometer according to the present invention using multipletwo-dimensional arrays sample holder;

FIG. 7 is a schematic representation of another embodiment of a massspectrometer according to the present invention;

FIG. 8 is a schematic representation of one embodiment of a massspectrometer according to the present invention using a single arraysample holder;

FIG. 9 is a schematic representation of an embodiment of a massspectrometer according to the present invention using a tapeconfiguration sample holder; and

FIG. 10 is a schematic representation of an embodiment of a massspectrometer according to the present invention using a diskconfiguration sample holder.

DETAILED DESCRIPTION OF SEVERAL EXEMPLARY EMBODIMENTS OF THE INVENTION

One aspect of the present invention is to provide a mass spectrometer inwhich the ion optics, ionizing source and optionally a detector aremovable relative to the sample holder held in a fixed position ratherthan translating the sample holder or sample stage relative to the massspectrometer which is held in a fixed position.

One embodiment of a mass spectrometer according to the present inventionis shown in FIG. 5. Mass spectrometer 50 is a time-of-flightspectrometer comprising ion source 52, ion detector 54, extractionelectrode 56 arranged proximate ion source 52, and a drift tube 58arranged between extraction electrode 56 and detector 54. The massspectrometer can further include an acceleration electrode 57.

The ion source 52 comprises a sample plate 60 and an ionizing source 62.The sample plate 60 can hold a sample of material 61 which can be asingle sample or a plurality of samples arranged in a one or twodimensional array configuration. The sample material 61 can be, forexample, a biomolecular material such as DNA, protein or the like. Thesample plate 60 is biased at relatively high voltage potential, forexample, 20 kV (the voltage is measured relative to the groundpotential). The sample plate can, for example, have a dimension of 5×3.4inches (approximately 12.7×8.64 cm).

The ionizing source 62 can be, for example, a radiation source such aslaser radiation, well suited for Matrix Assisted Laser DesorptionIonization (MALDI. Suitable lasers include lasers that emit in theultraviolet as these lasers ionize the sample efficiently.

The extraction electrode 56 comprises a grid electrode held at a voltagepotential relative to the sample plate 60 such that ions formed in thesample 61 are extracted and directed toward the entrance of drift tube58. The acceleration electrode is held at a same potential as drift tube58 which is in most situations connected to the ground or biased at somerelatively low voltage potential such as 0 to 100V.

The extraction electrode 56 is held at, for example, a potential of 15kV to 18 kV. If the potential at the sample plate 60 is 20 kV, thedifference of potential between the extraction electrode 56 and thesample plate 60 is 2 kV to 5 kV allowing the ions to acquire an initialkinetic energy of 2 keV to 5 keV (for singly charged ions).

The voltage of the sample plate 60 or the voltage of the extractionelectrode 56 can be pulsed. Pulsing the sample plate voltage or theextraction voltage allows achieving better focusing of the ions. Variouspulsing schemes exist, this includes several variations of voltagewaveforms (e.g., linear, exponential) as well as adjusting the delaytime of the voltage pulse relative to the laser pulse (in MALDI).Exemplary ion pulsing extraction methods have been described in acommonly assigned U.S. Pat. No. 6,518,568, the entire contents of whichare incorporated herein by reference.

During operation, the mass spectrometer 50 is enclosed inside vacuumchamber 65 to allow collisionless movement of ions formed in ion source52. The vacuum chamber 65 is pumped with pump 66 and pressure is keptbellow 5×10⁻⁷ Torr. Although the chamber 65 is illustrated in FIG. 5 ashaving a cylindrical shape, other geometrical shapes are also within thescope of the present invention.

The drift tube 58 is also cylindrical in shape, however other shapes arealso within the scope of the present invention. The drift tube is madeof an electrically conductive metal such as stainless-steal or the like.The drift tube 58 is maintained at nearly ground potential to allow freemovement of the ions traveling therethrough. The drift tube 58 may alsobe biased to a relatively low voltage potential (0 to 100 V) to allowadditional focusing of the ion beam. The longitudinal dimension of thedrift tube can be for example 3 inches (approximately 7.6 cm) and thediameter of the tube can be, for example, 0.5 inch (approximately 1.27cm).

The detector 54 can be selected from any commercially available chargedparticles detector. Such detectors include, but are not limited to, anelectron multiplier, a channeltron or a micro-channel plate (MCP)assembly. Although, a micro-channel plate is shown used as the detectorin FIG. 5, one skilled in the art would readily understand that usingother detectors are also within the scope of the present invention.

An electron multiplier is a discrete dynode with a series of curvedplates facing each other but shifted from each such that an ion stringone plate creates secondary electrons and an effect of electronavalanche follows through the series of plates. A channeltron is ahorn-like continuous dynode structure that is coated on the inside withan electron emissive material. An ion striking the channeltron createssecondary electrons that have an avalanche effect to create moresecondary electrons and finally a current pulse.

A microchannel plate is made of a leaded-glass disc that containsthousands or millions of tiny pores etched into it. The inner surface ofeach pore is coated to facilitate releasing multiple secondary electronswhen struck by an energetic electron or ion. When an energetic particlesuch as an ion strikes the material near the entrance to a pore andreleases an electron, the electron accelerates deeper into the porestriking the wall thereby releasing many secondary electrons and thuscreating an avalanche of electrons.

In most applications, two channel plates are assembled to provide anincreased gain of electrons. In the embodiment shown in FIG. 5, a MCPassembly is used as the ion detector 54. An exit electrode grid 64 isprovided in front of the MCP assembly. Electrode grid 64 is maintainedat substantially the same potential as the drift tube 58.

The detected electron signal corresponding to an ion striking thedetector is further amplified, integrated, digitized and recorded into amemory for later analysis and/or displayed through a graphical interfacefor evaluation.

The mass spectrometer 50 consists of detecting the arrival of the ionsat the detector 54 and measuring their time-of-flight in reference tofiring the laser pulse or the application of a voltage pulse to thesample plate 60 or extraction electrode 56. The voltage pulse applied tothe sample plate 60 or extraction electrode 56 may be delayed relativeto the laser pulse to increase efficiency of ion extraction. Since, asexplained above, the time-of-flight is proportional to the square rootof the mass of the ions, knowing the time-of-flight allows thedetermination of the mass of the ions and thus the identification of theions.

In this embodiment, the sample holder or sample plate 60 is fixedrelative to the walls of the vacuum chamber 65 and the extractionelectrode 56, acceleration grid 57, drift tube 58, and detector 54 moveas one assembly 68 (mass analyzer assembly) relative to the sample plate60 in order to scan across the array of samples 61. The mass analyzerassembly 68 moves both in the X direction as well as the Y direction toallow scanning of selected samples in an area of sample plate or sampleholder 60. During scanning of the sample plate 60, the mass analyzerassembly 68 is arranged such that the symmetry axis AA′ of assembly 68is always maintained substantially perpendicular to each of the samples61.

During scanning of the sample plate 60, the ionizing source (e.g. laser)62 tracks the movement of the assembly 68 in order to ionize eachselected sample. The movement of the laser beam emitted from the lasercan be accomplished, for example, by using articulated assembly 63comprised of articulated optics that brings the laser beam to a focusinglens (not shown) mounted on the mass analyzer assembly 68.Alternatively, the laser beam can be directed to the sample by using asuitable optical fiber wherein at least a portion of the optical fiberis coupled to the mass analyzer assembly 68.

Another embodiment of a mass spectrometer according to the presentinvention is shown in FIG. 6. Mass spectrometer 70 is similar the massspectrometer 50 except that in mass spectrometer 70, the sample holder72 is used to hold a plurality of sample micro-arrays 74. In turn, eachsample micro-array contains a plurality of samples 76. Thisconfiguration is used in the case where very high sample density isneeded.

Similarly to mass spectrometer 50, mass spectrometer 70 comprises massanalyzer assembly 78. Mass analyzer assembly 78 is movable relative tothe sample holder 72. The mass analyzer is capable of scanning all ofthe samples 76 in the sample holder 72 by moving the mass analyzerassembly in the X and Y direction over each of the sample micro-arrays74 and then fine tuning the movement of the mass analyzer assembly 78 inthe X and Y directions to scan each of the samples 76.

Another embodiment of a mass spectrometer according to the presentinvention is shown in FIG. 7. Mass spectrometer 80 is similar to massspectrometers 50 and 70 except that in mass spectrometer 80, thedetector 82 is not part of mass analyzer assembly 84. Mass analyzerassembly 84 comprises extraction electrode 86, drift tube 88 andoptionally acceleration electrode (grid electrode) 90. Detector 82comprises a micro-channel plates assembly similar to the MCP assemblydescribed in the previous embodiments.

Similarly to the previous embodiments, mass analyzer assembly 84 ismovable relative to sample holder 92. The mass analyzer assembly 84 iscapable of scanning selected samples 94 in sample holder 92 by movingthe mass analyzer assembly 84 in the X and Y direction over the selectedsamples 94.

During scanning of the sample holder 92, the ionizing source (laserbeam) 96 tracks the movement of the assembly 84 in order to ionize eachselected sample 94. In this embodiment, the laser beam 96 is directed tothe selected sample via optical fiber 97 which is coupled to the massanalyzer assembly 84 to follow the movement of the mass analyzerassembly 84.

In mass spectrometer 80, however contrary to mass spectrometers 50 and70, the detector 82, which comprises a MCP assembly, does not move withmass analyzer assembly 84. Therefore, in order to detect ions formed byionization of the material in each of the samples 94, the MCP assemblyin detector 82 is selected to have a substantially larger size than thesize of sample holder 92. In other words, the MCP assembly in detector82 has an area size which substantially “covers” the whole area ofsample holder 92.

Another embodiment of a mass spectrometer according to the presentinvention is shown in FIG. 8. Mass spectrometer 100 is similar to massspectrometers 50 and 70 except that in mass spectrometer 100, the sampleholder 102 is a “slide” having a one dimensional array of samples 104.

Similarly to mass spectrometer 50, mass spectrometer 100 comprises massanalyzer assembly 106. Mass analyzer assembly 106 is movable relative tothe sample holder 102. The mass analyzer assembly 106 is capable ofscanning all of the samples 104 in the sample holder 102 by moving themass analyzer assembly 106 in the X direction over each of the samples104. Fine translation along the X and Y directions is used to positionthe mass analyzer assembly 106 above a selected area of the sample spot.Fine movement in X and Y directions within a sample allows analyzing aspecific spot in the selected sample.

Another embodiment of a mass spectrometer according to the presentinvention is shown in FIG. 9. Mass spectrometer 110 is similar to massspectrometers 100 except that in mass spectrometer 110, the sampleholder 112 is a continuous tape having a one dimensional array ofsamples 114. In this configuration, the continuous tape 112 isintroduced into vacuum chamber 118 through opening or slit 119A in awall of the vacuum chamber 118 and exits through opening or slit 119B invacuum chamber 118. Openings 119A and 119B are provided with seals toseal a portion of the tape 112 under study in vacuum chamber 118.Although the motion of the tape might accomplish sample selection,translating the mass analyzer assembly 116 would provide the additionalability to analyze specific locations or spots within each sample.

In another configuration, the tape 112 may be rolled in a cassette (notshown), for example, and the whole cassette may be introduced into thevacuum chamber 118. Alternatively, the cassette having the tape 112 maybe disposed outside the vacuum chamber 118 and the tape 112 isintroduced through opening 119A rolled back to cassette through exitopening 119B. A further option, is to pump the vacuum chamber each timethe mass spectrometer 110 comes sealingly in contact with the surface ofthe tape 112 to perform mass analysis of a sample and break the vacuumto allow the mass spectrometer to move to a next sample. By repeatingthis process one can scan a selected block of samples.

Another embodiment of a mass spectrometer according to the presentinvention is shown in FIG. 10. Mass spectrometer 120 is similar to massspectrometers 50, 70, 100 except that in mass spectrometer 120, thesample holder 122 is a disk, such as that of a CD ROM. In thisconfiguration, the disk 122 holds a plurality of samples 124 arrangedconcentrically around opening 126. The disk 122 is fixed via opening 126to a stand and/or a rotor to allow rotation of the disk around an axisZZ′ passing through the center of opening 126 and perpendicular to theplane of the disk 122.

Similarly to mass spectrometers 50, 70 and 100, mass spectrometer 120comprises mass analyzer assembly 128. Mass analyzer assembly 128 ismovable relative to the disk 122. The mass analyzer is capable ofscanning all of the samples 124 in the disk 122 by moving the massanalyzer assembly 128 in a radial direction R to scan all samples inthat radial direction R and rotating the disk azimuthally at angle θ tothe next radial direction R′ and scan the samples in that radialdirection R′. By repeating this process one can scan all the samples 124in disk 122 or scan selected samples 124 by skipping radial positions Rand/or angular positions θ. In this configuration, the mass analyzerassembly 128 does not move azimuthally. In an alternative embodiment,the disk 122 can remain in a fixed position and in order to scan all thesamples in the disk, the mass analyzer assembly is moved both radially(R) and azimuthally (θ).

By allowing the mass analyzer to move instead of the sample holder, therelative size of a mass spectrometer according to the present inventionis substantially reduced. Consequently, the volume pumped by the vacuumpumping system is reduced. This, in turn, allows further increasedminiaturization of the mass spectrometer.

Although the mass spectrometer of the present invention is shown invarious specific embodiments, one of ordinary skill in the art wouldappreciate that variations to these embodiments can be made thereinwithout departing from the spirit and scope of the present invention.For example, although the mass spectrometer has been described with theuse of a laser as an ionizing source, one of ordinary skill in the artwould appreciate that using electrospray, atmospheric pressureionization (API) and atmospheric MALDI (APMALDI) is also within thescope of the present invention. The many features and advantages of thepresent invention are apparent from the detailed specification and thus,it is intended by the appended claims to cover all such features andadvantages of the described apparatus which follow the true spirit andscope of the invention.

Furthermore, since numerous modifications and changes will readily occurto those of skill in the art, it is not desired to limit the inventionto the exact construction and operation described herein. Moreover, theprocess and apparatus of the present invention, like related apparatusand processes used in mass spectrometry arts tend to be complex innature and are often best practiced by empirically determining theappropriate values of the operating parameters or by conducting computersimulations to arrive at a best design for a given application.Accordingly, all suitable modifications and equivalents should beconsidered as falling within the spirit and scope of the invention.

1. A mass spectrometer, comprising: an ionizing source; a sample holderarranged in a beam path of said ionizing source; an ion detectordisposed to receive ions extracted from a sample when held by saidsample holder and irradiated by said ionizing source; an extractionelectrode arranged proximate said sample holder; and a drift tubearranged between said extraction electrode and said ion detector,wherein said extraction electrode and said drift tube are movabletogether relative to said sample holder; said sample holder being heldat a fixed position.
 2. A mass spectrometer as recited in claim 1,further comprising an acceleration electrode disposed between saidextraction electrode and said drift tube.
 3. A mass spectrometer asrecited in claim 1, wherein said sample holder is configured to hold aplurality of samples.
 4. A mass spectrometer as recited in claim 3,wherein said plurality of samples are arranged in a single row and saidsample holder is a tape-like structure.
 5. A mass spectrometer asrecited in claim 3, wherein said plurality of samples are arranged in atwo-dimensional array on said sample holder.
 6. A mass spectrometer asrecited in claim 3, wherein said plurality of samples are arranged in aplurality of two dimensional arrays on said sample holder.
 7. A massspectrometer as recited in claim 3, wherein said sample holder is a diskhaving an opening suitable for mounting on a rotating assembly.
 8. Amass spectrometer as recited in claim 7, wherein said plurality ofsamples are arranged concentrically around said opening and saidextraction electrode and said drift tube are movable in a radialdirection of said disk relative to said opening.
 9. A mass spectrometeras recited in claim 1, further comprising a vacuum chamber, wherein saidion detector, said extraction electrode and said drift tube are disposedinside said vacuum chamber.
 10. A mass spectrometer as recited in claim9, wherein said sample holder is a continuous tape which is sealinglyintroduced into said vacuum chamber through an opening in a wall of saidvacuum chamber.
 11. A mass spectrometer as recited in claim 9, whereinsaid sample holder is a continuous tape in a tape-cassette and said tapecassette is disposed in said vacuum chamber.
 12. A mass spectrometer asrecited in claim 1, wherein said extraction electrode is a gridelectrode.
 13. A mass spectrometer as recited in claim 1, furthercomprising a sample holder voltage source, wherein said sample holder isconnected to said sample holder voltage source to establish a sampleholder voltage potential relative to the ground potential.
 14. A massspectrometer as recited in claim 13, wherein said sample holder voltagepotential is pulsed.
 15. A mass spectrometer as recited in claim 13,further comprising an extraction voltage source, wherein said extractionelectrode is connected to said extraction voltage source to establish anextraction voltage potential relative to the voltage potential of saidsample holder.
 16. A mass spectrometer as recited in claim 15, whereinsaid extraction electrode voltage potential is pulsed.
 17. A massspectrometer as recited in claim 1, further comprising a drift tubevoltage source, wherein said drift tube is connected to said drift tubevoltage source to establish a drift tube voltage potential.
 18. A massspectrometer as recited in claim 2, further comprising an accelerationelectrode voltage source, wherein said acceleration electrode isconnected to said acceleration voltage source to establish a voltagepotential substantially equal to a voltage potential of said drift tube.19. A mass spectrometer as recited in claim 1, wherein said ion detectorcomprises an electron multiplier.
 20. A mass spectrometer as recited inclaim 1, wherein said ion detector comprises a channeltron.
 21. A massspectrometer as recited in claim 1, wherein said ion detector comprisesa micro-channel plate assembly.
 22. A mass spectrometer as recited inclaim 1, wherein said ion detector is movable together with saidextraction electrode and said drift tube relative to said sample holder.23. A mass spectrometer as recited in claim 1, wherein said ion detectoris fixed in a substantially stationary position relative to said sampleholder.
 24. A mass spectrometer as recited in claim 23, wherein said iondetector is a micro-channel plate assembly.
 25. A mass spectrometer asrecited in claim 24, wherein said micro-channel plate assembly has adetection area substantially subtending an area of said sample holder.26. A mass spectrometer as recited in claim 1, wherein said ionizingsource comprises a laser.
 27. A mass spectrometer as recited in claim26, further comprising a tracking assembly, wherein said laser tracks amovement of said extraction electrode and said drift tube with saidtracking assembly such that a laser beam emitted by the laser isdirected upon the sample which is directly under said extractionelectrode.
 28. A mass spectrometer as recited in claim 26, furthercomprising an optical fiber, wherein said laser tracks a movement ofsaid extraction electrode and said drift tube by directing a laser beamemitted by the laser with said optical fiber upon the sample which isdirectly under said extraction electrode.
 29. A mass spectrometer asrecited in claim 1, further comprising a vacuum chamber, wherein saidvacuum chamber is pumped down to a pressure such that ions formed byionization of said sample with said ionizing source move freely in saidvacuum chamber toward said ion detector.
 30. A method of analyzing aplurality of samples disposed on a sample holder by a mass spectrometercomprising an ionizing source, an ion detector, an extraction electrodearranged proximate to the sample holder, and a drift tube arrangedbetween the extraction electrode and the ion detector, the methodcomprising: positioning said extraction electrode and said drift tubeabove a first sample in said plurality of samples; ionizing said firstsample with said ionizing source to form a plurality of first ions;detecting first ions from said plurality of first ions with said iondetector; identifying at least a portion of said first ions detected;moving at least said extraction electrode and said drift tube togetherrelative to said sample holder to a second sample of said plurality ofsamples; ionizing said second sample with said ionizing source to form aplurality of second ions; detecting second ions from said plurality ofsecond ions with said ion detector; and identifying at least a portionof said second ions detected.